Prodrugs for a selective cancer therapy

ABSTRACT

The chemotherapy of malignant tumours is greatly restricted by the generally slight differentiation of the available cytostatic agents between normal and malignant tissue. In order to achieve an improvement of the selectivity in cancer therapy, novel prodrugs have been developed from 6-hydroxy-2,3-dihydro-1H-indolene, 5-hydroxy-1,2-dihydro-3H-pyrrolo[3,2-e]indolene and 5-hydroxy-1,2-dihydro-3H-benzo[e]indolene as well as from 6-hydroxy-1,2,3,4-tetrahydro-benzo[f]-quinolines, that may be used within the framework of the ADEP therapy (antibody directed enzyme prodrug therapy). The new prodrugs are characterised by a high difference in toxicity between the prodrug and underlying drug and by a very high efficacy of the drug. After splitting off of the glycosidic and/or acetal group on the phenolic hydroxy groups of the prodrugs, a spirocyclopropacyclohexadiene is formed which, being a highly toxic group, effects an alkylation of the DNA or RNA.

CROSS REFERENCE TO RELATED APPLICATION

This application is a national stage of PCT/EP01/04904 filed May 2,2001.

BACKGROUND OF THE INVENTION

1. Field of the Invention

It is known that cancer chemotherapeutic agents available at the presenttime produce undesirable side effects on account of their lowselectivity, that limit the dose that can be applied or may even lead toa discontinuation of the treatment. The aim must therefore be to utilisegenetic and phenotype differences between normal and malignant cells inorder to achieve a higher selectivity.

2. Description of the Related Art

For this purpose prodrugs may be used that are either acid-catalysed bythe pH value reduced by 1 to 2 units in tumour cells or that can besplit within the scope of the ADEPT concept (antibody directed enzymeprodrug therapy), which is based on the utilisation of conjugates ofglycohydrolases and monoclonal antibodies that bind to tumour-associatedantigens [see Pharmacology & Therapeutics 83, 67–123, (1999); J. Biol.Chem. 272, 15804–15816, (1997); J. Med. Chem. 41, 1507–1512, (1998);Bioconjug. Chem. 98, 255–259, (1998); Cancer Immunol. Immunother. 44,305–315, (1997)]. In this connection cytotoxic compounds are used thatare detoxified by conversion into enzymatically splitable derivatives(prodrugs). The enzyme-antibody conjugates are selectively present,after their administration, on the surface of the cancer cells and splitthe prodrugs only in the tumour, with the release of the cytotoxiccompound.

As cytotoxic compounds there have inter alia already been usedderivatives of the seco-CI analogue of the natural substance CC-1065that have been converted, inter alia as galactocides, into correspondingprodrugs. Glycohydrolases inter alia have been used for theantibody-enzyme conjugates [see Angew. Chem. 108, 2840–2842, (1996);Angew. Chem. Int. Ed. Engl. 35, 2674–2677, (1996)]. Essential criteriafor the successful use of prodrugs within the framework of the ADEPTconcept are the low toxicity of the prodrugs, a very high cytotoxicityof the underlying cytostatic agent, and a rapid splitting of the prodrugin the presence of the corresponding enzyme.

It is furthermore known that malignant cells exhibit an enhancedglycolysis and thus lactate production compared to normal tissue, andthat the pH in the tumour tissue can be lowered by intravenously appliedglucose [see S. Tanneberger, Experimentelle und klinischeTumorchemotherapie; Allgemeine Tumorchemotherapie; G. Fischer Verlag,Stuttgart/New York 1980; Naturwiss. 46, 2 (1959); Cancer Res. 42, 1498(1982); 42, 1505 (1982); 49, 4373 (1989)].

It is also known that numerous glycohydrolases in a slightly acidicmedium have a higher activity than at pH 7.4. Such glycohydrolases mayalso be bound to monoclonal antibodies that bind selectively to specifictumour-associated antigens on the membrane of malignant cells [seePharmacology & Therapeutics 83, 67 (1999)].

In the past attempts have been made to utilise these differences in thepH value between normal tissue and tumour tissue for a selective tumourtherapy [see Cancer Res. 49, 4179, (1989); Liebigs Ann. Chem. 847(1987); Tetrahedron Lett. 22, 239, (1981); Angew. Chem. 102, 812,(1990); Liebigs Ann. Chem. 151, (1990)]. The acid-labile non-toxicprodrugs used for this purpose that are obtained from alkylatingcompounds have however proved not to be sufficiently acid-labile thatthey can be split selectively in the tumour tissue to form an activecytocidal agent.

Attempts have also been made to convert cytotoxic compounds byderivatisation into enzymatically splitable prodrugs having a reducedtoxicity. With the previously synthesised compounds the problem arosethat either the differences in the cytotoxicity of the prodrug and theunderlying drug were not sufficient, and/or the drug was notsufficiently effective [see Angew. Chem. 108, 2840, (1996)].

In contrast to this the acid-catalysed prodrugs or prodrugsenzymatically splitable preferably with glycohydrolases proposed in thepresent invention that are obtained from6-hydroxy-2,3-dihydro-1H-indolene,5-hydroxy-1,2-dihydro-3H-pyrrolo[3,2-e]indolene and5-hydroxy-1,2-dihydro-3H-benzo[e]indolene as well as from6-hydroxy-1,2,3,4-tetrahydro-benzo[f]-quinoline derivatives unexpectedlyexhibit a selectivity, not hitherto found, of more than 1:1500 betweenthe prodrug and the cytostatic agent on which the prodrug is based,combined at the same time with a high cytotoxicity of the cytostaticagent in the cell culture.

SUMMARY OF THE INVENTION

The present invention relates to novel substituted6-hydroxy-2,3-dihydro-1H-indoles of the general formula (I), novelsubstituted 5-hydroxy-1,2-dihydro-3H-pyrrolo[3,2-e]indoles of thegeneral formula (II) and novel substituted 5-hydroxy-1,2-dihydro-3H-benzo[e]indoles of the general formula (III) as well as theirO-glycosides with monosaccharides, disaccharides and oligosaccharides ofthe general formulae (IV), (V) and (VI), and novel O-glycosides withmonosaccharides, disaccharides and oligosaccharides of6-hydroxy-1,2,3,4-tetrahydro-benzo[f]-quinolines of the general formula(VII) as well as 6-hydroxy-1,2,3,4-tetrahydro-benzo[f]-quinolines of thegeneral formula (VIII) according to claim 1, processes for theirproduction according to claims 4 and 8, and their use as highlyselective cytostatic agents in cancer therapy according to claims 9 and10.

Advantageous embodiments of the new compounds and of the new process aredescribed in the subclaims 2 and 3, and 5 to 7.

BRIEF DESCRIPTION OF THE DRAWINGS

Other objects, features and advantages of the present invention willbecome apparent upon reading the following detailed description, whilereferring to the attached drawings, in which:

FIG. 1 is a graph showing the antiproliferation action ofseco-Methyl-CBI-II-Gal derivatives, with and without β-D-galactosidase,on human bronchial carcinoma cells of line A549.

FIG. 2 is a graph showing the antiproliferation action ofseco-CBC-II-Gal derivatives, with and without β-D-galactaaidase, onhuman bronchial carcinoma cells of line A549.

DETAILED DESCRIPTION OF THE INVENTION

Within the scope of the present invention a hydroxy protective groupgenerally denotes a protective group from the following list:tert.-butoxydiphenylsilyl, trimethylsilyl, triethylsilyl,triisopropylsilyl, tert.-butyldimethylsilyl, tert.-butyldiphenylsilyl,triphenylsilyl, tri-methylsilylethoxycarbonyl, benzyl,benzyloxycarbonyl, 2-nitrobenzyl, 4-nitrobenzyl,2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl,tert.-butyloxycarbonyl, allyl-oxycarbonyl, 4-methoxybenzyl,4-methoxybenzyloxycarbonyl, formyl, acetyl, trichloroacetyl,2,2,2-trichloroethoxycarbonyl, 2,4-dimethoxybenzyl,2,4-dimethoxybenzyloxycarbonyl, methylthiomethyl, methoxyethoxymethyl,[2-(trimethylsilyl)ethoxy]methyl, 2-(methylthiomethoxy)ethoxycarbonyl,benzoyl, 4-methylbenzoyl, 4-nitrobenzoyl, 4-fluorobenzoyl,4-chlorobenzoyl or 4-methoxybenzoyl. Acetyl, benzoyl, benzyl ormethylbenzyl are preferred.

Amino-protective groups within the scope of the present invention arethe conventional amino-protective groups used in peptide chemistry.These preferably include: benzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl, methoxycarbonyl, ethoxycarbonyl,propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl,tert.-butoxycarbonyl, allyloxycarbonyl, vinyloxycarbonyl,2-nitrobenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl,cyclohexoxycarbonyl, 1,1-dimethylethoxycarbonyl, adamantylcarbonyl,phthaloyl, 2,2,2-trichloroethoxycarbonyl,2,2,2-trichlorotertbutoxycarbonyl, menthyloxycarbonyl, phenoxycarbonyl,4-nitrophenoxycarbonyl, fluoroenyl-9-methoxycarbonyl, formyl, acetyl,propionyl, pivaloyl, 2-chloroacetyl, 2-bromoacetyl,2,2,2-trifluoroacetyl, 2,2,2-trichloroacetyl, benzoyl, 4-chlorobenzoyl,4-bromobenzoyl, 4-nitrobenzoyl, phthalimido, isovaleroyl orbenzyloxymethylene, 4-nitrobenzyl, 2,4-dinitrobenzyl or 4-nitrophenyl.Benzyloxycarbonyl, tert.-butoxycarbonyl and acetyl are preferred.

The process according to the invention for the production of the newcompounds of the general formulae (I), (II), (III), (IV), (V) and (VI)according to claim 4 may be illustrated by way of example by thefollowing reaction scheme:

The process according to the invention for the production of the newcompounds of the general formula (VII) may be illustrated by way ofexample by the following reaction scheme:

Suitable bases for the deprotonation within the meaning given above arealkali metal and alkaline earth metal hydrides, preferably sodiumhydride. Aprotic organic solvents are suitable as solvents, for exampledimethylformamide, tetrahydrofuran or diethyl ether. Dimethylformamideis preferred. The reaction is carried out in a temperature range from−30° C. to 80° C. under normal pressure, preferably at 0° C. to 80° C.

Cyclisation is carried out at normal pressure under an argon atmospherein a temperature range from 50° C. to 110° C., preferably at 80° C. to110° C., in the presence of tributyltin hydride. Suitable solvents arearomatic hydrocarbons, preferably benzene and toluene.α,α′-azo-isobutyronitrile is preferred as free-radical initiator.

The splitting off of the protective groups on the phenolic oxygen iscarried out by hydrogenolytic splitting, in the case of the benzyl groupin the presence of a catalyst, for example a mixture of palladium/C andpalladium/CaCO₃, with hydrogen or by addition of ammonium formate, inone of the solvents listed above, preferably tetrahydrofuran, methanolor acetone, in a temperature range from 0° C. to 60° C., preferably at20° C. to 50° C., or by lithium or sodium in liquid ammonia.

To produce the glycosidised prodrugs, the free phenol is coupled with aglycosyl donor. The donor may be selected from glycosyl halides,glycosyl tricholoroacetimidates or other suitable compounds.

Suitable promoters for the glycosidation are in general silver, mercuryand ammonium salts or Lewis acids, such as for example borontrifluoride/ethyl etherate, trimethysilyltrifluoromethane-sulfonate,boron tribromide or aluminium trichloride, and in the case of amidecoupling, carbodiimides such as for exampleN,N′-dicyclohexylcarbodiimide (DCC) orN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC).Boron trifluoride ethyl etherate and EDC are preferred.

Suitable promoters for the conversion with enol ethers are in generalsubstituted arylsulfonic acids such as for example naphthylsulfonicacid, p-toluenesulfonic acid (PTS) or pyridinium-p-toluenesulfonate(PPTS); PPTS and PTS are preferred.

Suitable solvents are organic solvents that ensure the solubility of therespective promoter. Suitable solvents include in general halogenatedhydrocarbons such as methylene chloride, chloroform or carbontetrachloride, or ethers such as for example diethyl ether,tetrahydrofuran and dioxane, as well as dimethyl sulfoxide ordimethylformamide.

In the case of the promoter boron triflouride/ethyl etherate it ispreferred to use methylene chloride and chloroform, and in the case ofEDC it is preferred to use dimethylformamide and dimethyl sulfoxide.

The promoter is used in an amount of 0.2 mole to 10.0 moles, preferably3.0 moles to 8.0 moles, referred to 1 mole of the compound of thegeneral formulae (I), (II) or (III).

The conversion is generally carried out at normal pressure under aninert gas atmosphere. It is however also possible to carry out theprocess under excess pressure or under reduced pressure (for example ina range from 0.5 to 5 bar).

The process according to the invention is generally carried out in atemperature range from −30° C. to +100° C.

Among derivatisations, deacetylations are carried out in order to splitoff the protective groups on the sugar.

The splitting off of the protective groups on the sugar radical iscarried out by a conventional method in inert solvents in the presenceof a base, or by hydrogenolysis.

Suitable bases for the splitting off are conventional inorganic bases.These preferably include alkali hydroxides or alkaline earth hydroxidessuch as for example sodium hydroxide, potassium hydroxide or bariumhydroxide, or alkali carbonates such as sodium or potassium carbonate orsodium hydrogen carbonate, or alkali alcoholates such as sodiumethanolate, sodium methanolate, potassium ethanolate, potassiummethanolate or potassium tert.-butanolate. Sodium methanolate orpotassium methanolate are particularly preferably used.

Suitable solvents for the splitting off are the conventional organicsolvents used for a saponification. These preferably include alcoholssuch as methanol, ethanol, propanol, isopropanol or butanol, or etherssuch as tetrahydrofuran or dioxane, or dimethylformamide or dimethylsulfoxide. Alcohols such as methanol, ethanol, propanol or isopropanolare particularly preferably used. It is also possible to use mixtures ofthe aforementioned solvents.

The splitting off is generally carried out in a temperature range from0° C. to +100° C., preferably from +20° C. to +60° C. In general thesplitting off is carried out under normal pressure. It is however alsopossible to operate under reduced pressure or under excess pressure (forexample from 0.5 to 5 bar).

The splitting off of special hydroxy protective groups (silyl groups andbenzyl groups) is performed for example with tetrabutylammonium fluorideor other fluoride compounds and/or by hydrogenolytic splitting, in thecase of the benzyl group in the presence of a catalyst, for example amixture of palladium/C and palladium/CaCO₃, with hydrogen, or byaddition of ammonium formate, in one of the solvents listed above,preferably tetrahydrofuran, methanol or acetone, in a temperature rangefrom 0° C. to 60° C., preferably at 20° C. to 50° C., or by lithium orsodium in liquid ammonia.

The splitting off of the amino protective groups is generally alsocarried out according to known methods, for example with Lewis acids indichloromethane.

The compounds of the general formulae (IX), (X) (XI), (XII), (XIII) (XX)and (XXI) are known per se and may be produced by methods described inthe literature.

The compounds of the general formulae (XIV), (XV), (XVI), (XVII),(XVIII) and (XIX) are novel and may be produced by the processesdescribed above.

The glycosides of 6-hydroxy-2,3-dihydro-1H-indoles of the generalformula (IV), the glycosides of5-hydroxy-1,2-dihydro-3H-pyrrolo[3,2-e]indoles (V), the glycosides of5-hydroxy-1,2-dihydro-3H-benzo[e]indoles (VI) and the glycosides of6-hydroxy-1,2,3,4-tetrahydrobenzo[f]-quinolines of the general formula(VII) as well as acetals of the6-hydroxy-1,2,3,4-tetrahydrobenzo[f]-quinolines of the general formula(VIII) constitute a largely non-toxic transport form for these highlycytocidal compounds. By using glycohydrolases that are preferablycoupled to tumour-specific monoclonal antibodies, and in the case of(VIII) by H⁺, the largely non-toxic transport forms are converted intothe highly cytocidal 6-hydroxy-2,3-dihydro-1H-indole or5-hydroxy-1,2-dihydro-3H-pyrrolo[3,2-e]indole or5-hydroxy-1,2-dihydro-3H-benzo[e]indole derivatives or6-hydroxy-1,2,3,4-tetrahydro-benzo[f]-quinolines with free phenolichydroxy groups. In this way it is possible, using a largely non-toxiccompound, selectively to release a cytocidal compound in the tumour, theconcentration of the cytocidal compound in the normal tissue being low.The dose-limiting side effects of the toxic6-hydroxy-2,3-dihydro-1H-indole or5-hydroxy-1,2-dihydro-3H-pyrrolo[3,2-e]indole or5-hydroxy-1,2-dihydro-3H-benzo[e]indole derivates or6-hydroxy-1,2,3,4-tetrahydrobenzo[f]-quinolines can be reduced in thisway.

Investigations of the Cytotoxicity

Cell Line: A 549

Substances:[3-((5′-(((1H-indol-2″-yl)-carbonyl)-amino)-1H-indol-2′-yl)carbonyl)-1-(1′-chloroethyl)-1,2-dihydro-3H-benz-[e]indol-5-yl]-β-D-galactopyranoside(seco-methyl-CBI-II-Gal) and2-chloro-4-[5′-(((1H-indol-2″-yl)-carbonyl)-amino)-1H-indol-2′-yl)carbonyl]-1,2,3,4-tetrahydrobenzo[f]quinolin-6-yl}-β-D-galactopyranoside(7, seco-CBC-II-Gal)

Cell culture: The cultivation of the cell line A 549 (ATCC no. CCL 185)in the form of monolayer cultures was carried out at 37° C. and 7.5% CO₂in air in DMEM (Dulbecco's Modified Eagle's Medium from Biochrom, orderno. TO43-10), that had been supplemented with 10% foetal calf serum(from Gibco).

Toxin exposure: The compounds were freshly dissolved with DMSO (Merck,order no. 2950.0500) before the experiment.

The toxin dilutions were carried out for pH 7.4 in DMEM. The pH value ofthe culture medium had previously been adjusted with 0.1 N HCl, takinginto account the pH fluctuations due to the CO₂ gassing. After the cellshad been added in concentrations of 10², 10³, 10⁴ and 10⁵ to 6-welltissue culture plates (Becton Dickinson, order no. 3046) and cultivateduntil adherence occurred, the culture was exposed to the toxin for 24hours in each case once with and once without the addition of 0.4unit/ml of β-D-galactosidase. Fresh culture medium, pH 7.4, was thenadded to the cells, which were cultivated for 12 days until theformation of macroscopically observable colonies. The colonies werefixed, stained with Löffler's Methylene Blue (Merck, order no. 1287) andcounted.

FIG. 1 and FIG. 2 show the results of the antiproliferation action oftwo inventive compounds on human bronchial carcinoma cells of lane A549.The results of the antiproliferation testing for seco-Methyl-CBI-II-Galderivatives both with and without β-D-galactosidase, are shown inFIG. 1. The results of thc antiproliferation testing for seco-CBC-Il-Galderivatives both with and without β-D-galactosidase, are shown in FIG.2.

seco-Methyl-CBI-II-Gal

Antiproliferative Action of Seco-methyl-CBI-II Deratives on HumanBronchial Carcinoma Cells of Line A549

Antiproliferative Action of Seco-CBC-II-Gal Deratives on Human BronchialCarcinoma Cells of Line A549

The present invention includes pharmaceutical preparations that contain,in addition to non-toxic, inert, pharmaceutically suitable carriers,also one or more compounds of the formulae (I), (II), (III), (IV), (V)and/or (VI), or which consist of one or more active substances of theformulae (I), (II), (III), (IV), (V) and/or (VI), (VII), (VIII), as wellas processes for the production of these preparations.

The active substances of the formulae (I), (II), (III), (IV), (V) and/or(VI) should be present in the pharmaceutical preparations listed abovein a concentration of about 0.1 to 99.5 wt. %, preferably about 0.5 to95 wt. % of the total mixture.

The pharmaceutical preparations listed above may contain, apart from thecompounds of the formulae (I), (II), (III), (IV), (V) and/or (VI),(VII), (VIII), also further pharmaceutical active substances.

The production of the pharmaceutical preparations listed above iscarried out in a conventional way by known methods, for example bymixing the active substance or substances with the carrier or carriers.

In general it has proved advantageous in both human medicine and inveterinary medicine to administer the active substance or substancesaccording to the invention in total amounts of about 0.5 to about 500,preferably 1 to 150 mg/kg body weight per 24 hours, optionally in theform of several individual doses, in order to achieve the desiredresults. An individual dose contains the active substance or substancespreferably in amounts of about 1 to about 100, in particular 1 to 80mg/kg body weight. It may however be necessary to deviate from theaforementioned dosages, and more specifically depending on the type andbody weight of the subject to be treated, the nature and severity of thedisease, the nature of the preparation and application of themedicament, as well as the period or time interval within which theadministration takes place.

Experimental Part

1. General Methods

Conversions were carried out where necessary in heated glass apparatusunder a slight argon excess pressure. The solvents were dried anddistilled corresponding to conventional laboratory procedures.Commercial products were used as a rule without further purification.

1.1 Equipment Used

Melting points: melting point determination apparatus FP61 from Mettler.The values are uncorrected.

Infrared spectra: Model IFS 25 from Bruker. Crystalline substances weremeasured as KBr pellets, and non-crystalline compounds as a film betweenKBr plates. Polystyrene bands at 1601 cm⁻¹ served for purposes ofcalibration.

UV/VIS spectra: Models Lambda 2 and Lambda 9 from Perkin-Elmer.

¹H-NMR spectra: Model AMX-300 (300 MHz) from Bruker and Model VXR-500(500 MHz) from Varian. The chemical shifts are given in δ-scale units.Tetramethylsilane (δ_(TMS)=0.00 ppm) served as internal standard. Thefollowing abbreviations are used to characterise the multiplicities ofthe signals: s (singlet), d (doublet), t (triplet), m (multiplet), m_(c)(centred multiplet), br (broad signal). The spectra were as a ruleinterpreted corresponding to first order. The coupling constants J aregiven in Hertz (Hz).

¹³C-NMR spectra: Model XL-200, VXR-200 (50.3 MHz), VXR-500 (125 MHz)from Varian, Model AMX-300 (75.5 MHz) from Bruker. Tetramethylsilane orthe specified solvent served as internal standard. The chemical shiftsare determined from the ¹H broadband-decoupled spectra, and the signalmultiplicities were determined in multiplet-selection experiments (APTpulse sequence).

Mass spectra: Model MAT 311A (low resolution spectra) and MAT 731 (highresolution spectra) from Varian. The relative intensities are given inbrackets referred to the base peak (I=100).

Elementary analyses: Hambloch Microanalytical Laboratory developed bythe Institute for Organic Chemistry, University of Göttingen.

1.2 Chromatographic Methods

Thin layer chromatography (TC): SIL G/UV₂₅₄ precoated TC sheets fromMachery, Nagel & Co. (layer thickness 0.25 mm) were used. R_(f) valuesare given (solvent height relative to the solvent front). The followingabbreviations are employed for the solvents that are used: EA (ethylacetate), PE (petroleum ether in the boiling point range 40–75° C.),CH₂Cl₂ (dichloromethane). In addition to the UV detection, avanillin-sulfuric acid solution (0.5 g vanillin, 3 ml sulfuric acid, 85ml methanol and 10 ml acetic acid) served as staining reagent.

Column filtration (CF) and column chromatography (CC): all columnchromatography-separations were carried out with silica gel 60 (grainsize: 0.063–0.200 mm) from Machery, Nagel & Co. or with silica gel 60(grain size: 0.200–0.400 mm). A substance/absorbent ratio of between50:1 and 200:1 was used depending on the separation task.

Explanation of the Abbreviations Used in the Experimental Part:

PE = Petrol ether EtOAc = Ethyl acetate DMF = Dimethylformamide EDC =N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride AIBN = α,α′-azoisobutyronitrile

PRODUCTION EXAMPLE Example 12-amino-4-benzyloxy-N-[E/Z-1′-(3′-chloro)-but-2′-enyl]-N-(tert.-butoxycarbonyl)-1-iodonaphthalene

400 mg (10.0 mmoles) of sodium hydride in the form of a 60% suspensionin paraffin oil were added to a solution of 2.00 g (4.21 mmoles) of2-amino-4-benzyloxy-N-(tert.-butoxycarbonyl)-1-iodonaphthalene [producedfor example according to D. L. Boger, J. A. McKie, J. Org. Chem. 1995,60, 1271] in 50.0 ml of dry DMF. The reaction mixture was stirred for 45minutes at room temperature and 1.20 ml (1.37 g, 10.9 mmoles) of anisomeric mixture of E/Z-1,3-dichlorobut-2-ene were added dropwise. Thereaction mixture was then stirred for 3 hours at room temperature. Afterhydrolysis with saturated NH₄Cl solution extraction was carried outthree times with EtOAc. The combined organic phases were washed fivetimes with water and then once with saturated NaCl solution and driedover Na₂SO₄. The solvents were removed in vacuo; a column chromatographypurification of the residue (100 g silica gel, 40–63 μm, solventPE/EtOAc 10:1) yielded 2.32 g (4.11 mmoles, 98% yield) of the targetcompound as a slightly yellowish oil.

R_(f)=0.40 (E) and 0.33 (Z) (PE/EtOAc 10:1)

Example 25-benzyloxy-3-(tert.-butoxycarbonyl)-1-(1′-chloroethyl)-1,2-dihydro-3H-benzo[e]indole

573 mg (1.02 mmoles) of the compound from Example 1 were dissolved in 18ml of dry, degassed toluene and 0.35 ml (384 mg, 1.32 mmoles) oftributyltin hydride and 42.0 mg (255 μmoles) of AIBN were added thereto.The mixture was heated to 80° C. and stirred for 3.5 hours at thistemperature. The residue obtained after concentration by evaporation wastaken up in diethyl ether and washed with the same volume of a 10%aqueous solution of KF. The residue obtained after drying the organicphase over Na₂SO₄ and removal of the solvents was subjected to a columnchromatography purification (100 g silica gel, 40–63 μm, solventPE/EtOAc 20:1). 187 mg (419 μmoles, 42% yield) of the syndiastereomerand 180 mg (411 μmoles, 41% yield) of the antidiastereomer of the targetcompound were obtained.R_(f)=0.52 (syn) and 0.32 (anti) (PE/EtOAc 10:1)

Example 3syn-3-(tert.-butoxycarbonyl)-1-(1′-chloroethyl)-5-hydroxy-1,2-dihydro-3H-benzo[e]indole

354 mg (808 μmoles) of the syn-isomer of the compound from Example 2were dissolved in 17.0 ml of acetone and 389 mg (366 μmoles) of 10% Pdon activated charcoal as well as 318 mg (5.05 mmoles) of ammoniumformate were added thereto. The reaction mixture was stirred for 2 hoursat 50° C. The reaction solution was filtered through celite that hadbeen thoroughly washed with EtOAc. The residue obtained afterconcentrating the filtrate by evaporation was purified by columnchromatography on silica gel (40 g, 40–63 μm, solvent PE/EtOAc 5:1) andthereby yielded 111 mg (320 μmoles, 85% yield) of the target compound.

R_(f)=0.48 (PE/EtOAc 5:1)

Example 4syn-[3-((5′-(((1H-indol-2″-yl)carbonyl)amino)-1H-indol-2′-yl)carbonyl)-1-(1′-chloroethyl)-1,2-dihydro-3H-benzo[e]indol-5-yl]-2,3,4,6-tetra-O-acetyl-β-D-galactopyranoside

50.0 mg (144 μmoles) of the compound from Example 3 were dissolved in7.0 ml of dry dichloromethane. 1.00 g of thoroughly heated molecularsieve (4Å) as well as 74.0 mg (148 μmoles) ofO-(2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl)-trichloroacetimidatewere added thereto. The reaction mixture was stirred for 30 minutes atroom temperature, following which 59.0 μl (66.7 mg, 470 μmoles) of borontrifluoride ethyl etherate were added slowly at −10° C. The reactionmixture was stirred for a further 1 hour at −10° C., and then for 4hours at room temperature. The mixture was concentrated by evaporationto dryness under a high vacuum and then suspended under an argonatmosphere in 2.5 ml of dry, degassed DMF. 40.9 mg (128 μmoles) of5-[((1H-indol-2′-yl)carbonyl)amino]-1H-indole-2-carboxylic acid as wellas 62.0 mg (320 μmoles) of EDC were added and the whole was stirred for36 hours at room temperature. The mixture was concentrated byevaporation to dryness and the residue was subjected to columnchromatography on silica gel (50 g, 40–63 μm, solvent 33–66% EtOAc inPE). 69.5 mg (79.0 μmoles, 55% yield) of the target compound wereobtained.

R_(f)=0.58 (PE/acetone/methanol 10:6:1)

Example 5syn-[3-((5′-(((1H-indol-2″-yl)carbonyl)amino)-1H-indol-2′-yl)carbonyl)-1-(1′-chloroethyl)-1,2-dihydro-3H-benzo[e]indol-5-yl]-β-D-galactopyranoside

64.0 mg (72.5 μmoles) of the compound from Example 4 were dissolved in2.0 ml of dry methanol and 9.0 μl (48.6 μmoles) of a 5.4 M solution ofsodium methanolate in methanol were added. After stirring for 3 hours atroom temperature 0.5 ml of water was added and the precipitate wasfiltered off. 19.2 mg (27.0 μmoles, 37% yield) of the target compoundwere obtained.

Example 6

Alcohol 1 is known in the literature (D. L. Boger, J. A. McKie, C. W.Boyce, Synlett 1997, 515–517) and was obtained in a slightly modifiedsynthesis sequence according to conventional laboratory procedures.

6-benzyloxy-2-(tert-butyldiphenylsilanyloxy)-N-(tert-butoxycarbonyl)-2,3-dihydro-1H-benzo[f]quinoline(2)

A solution of the alcohol 1 in absolute DMF (5 ml) was added to amixture of imidazole (1.47 g, 21.6 mmoles, 5 equivs.) andtert-butyldiphenylsilyl chloride (2.21 ml, 2.37 g, 8.63 mmoles, 2equivs.) and the reaction mixture was stirred for three days at roomtemperature. The reaction mixture was worked up by adding the yellowsolution to iced water and was extracted twice with CH₂Cl₂ and once withEt₂O. The combined organic phases were washed three times with saturatedcitric acid solution and then with saturated NaCl solution, dried overMgSO₄, and the solvent was removed in vacuo. The oily yellow crudeproduct thus obtained yielded after column chromatography purification(PE/EE=30:1) 2.60 g (94%) of the silyl ether 2 in the form of a whitesolid foam.

R_(f)=0.59 (PE/EE=3:1), brown (VSS);

UV (CH₃CN): λ_(max)(lg ε)=253 nm (3.859), 303 (3.089)

IR (KBr): ñ=3070 cm⁻¹ (Ar—H), 2930 (CH), 1702 (C═O), 1595, 1367, 1254,1158, 757.

¹H-NMR (300 MHz, CDCl₃): δ=1.08 (s, 9 H, SiC(CH₃)₃), 1.46 (s, 9 H,OC(CH₃)₃), 2.90 (dd, J=17.0, 6.4 Hz, 1 H, 1-H_(a)), 3.05 (dd, J=17.0,6.0 Hz, 1 H, 1-H_(b)), 3.62 (dd, J=12.5, 8.3, Hz, 1 H, 3-H_(a)), 4.00(dd, J=12.5, 3.0 Hz, 1 H, 3-H_(b)), 4.29 (dddd, J=8.3, 6.4, 6.0, 3.0 Hz,1 H, 2-H), 5.19 (s, 2 H, CH₂Ph), 7.22 (s, 1 H, 5-H), 7.32–7.48 (m, 11 H,5×Bn-H, 4×Ph-H_(m), 2×Ph-H_(p)), 7.52–7.54 (m, 2 H, 8-H, 9-H), 7.59 (d,J=8.3 Hz, 1 H, 10-H), 7.70–7.75 (m, 4 H, 4×Ph-H_(o)), 8.29 (dd, J=8.3,1.1 Hz, 1 H, 7-H).

¹³C-NMR (50 MHz, CDCl₃): δ=19.22 (SiC(CH₃)₃), 26.98 (SiC(CH₃)₃), 28.39(OC(CH₃)₃), 33.76 (C-1), 50.24 (C-3), 66.69 (C-2), 70.10 (CH₂Ph), 80.93(OC(CH₃)₃), 103.8 (C-5), 113.7 (C-10b), 122.3, 122.4, 124.1 (C-7, C-10,C-8), 123.4 (C-6a), 127.8 (C-9), 127.6 (2×Bn-C_(o)), 127.7 (4×Ph-C_(m)),127.9 (Ph-C_(p)), 128.5 (2×Bn-C_(m)), 129.8 (2×Ph-C_(p)), 132.6 (C-10a),133.7, 134.0 (2×Ph-C_(i)), 135.7 (4×Ph-C_(o)), 135.8 (Bn-C_(i)), 137.1(C-4a), 152.3 (C═O), 154.9 (C-6).

MS (DCI, NH₃): m/z (%)=661 (70) [M+NH₄]⁺, 644 (12) [M+H]⁺, 605 (22) 274(100).

C₂₅H₂₇NO₄ (387.47). calc.: C: 76.48 H: 7.05 N: 2.18 found: C: 76.35 H:7.29 N: 2.12

2-(tert-butyldiphenylsilanyloxy)-6-hydroxy-4-(tert-butoxycarbonyl)-2,3-dihydro-1H-benzo[f]quinoline(3)

Ammonium formate (1.65 g, 26.3 mmoles, 6.5 equivs.) and 10% Pd onactivated charcoal (2.15 g, 2.02 mmoles, 0.5 equiv.) were added to asolution of the benzyl ether 2 (2.60 g, 4.04 mmoles) in acetone (100 ml)and refluxed for one hour. After cooling to room temperature thecatalyst was filtered off through celite and thoroughly rewashed withacetone. After removing the solvent in vacuo and column filtration(PE/EE=5:1) 2.22 g (99%) of a white foam were obtained.

Mp.: 71–73° C.

R_(f)=0.40 (PE/EE=5:1), yellow (VSS);

UV (CH₃CN): λ_(max) (lg ε)=253 nm (3.842), 299 (2.986), 271 (2.777).

IR (KBr): ñ=3372 cm⁻¹ (OH), 3070 (Ar—H), 2931(CH), 1675 (C═O), 1597,1368, 1256, 1156, 758.

¹H-NMR (300 MHz, CDCl₃): δ=1.03 (s, 9 H, SiC(CH₃)₃), 1.37 (s, 9 H,OC(CH₃)₃), 2.83 (dd, J=16.6, 6.8 Hz, 1 H, 1-H_(a)), 2.99 (dd, J=16.6,6.4 Hz, 1 H, 1-H_(b)), 3.49 (dd, J=12.4, 8.3 Hz, 1 H, 3-H_(a)), 3.94(dd, J=12.4, 3.4 Hz, 1 H, 3-H_(b)), 4.29 (dddd, J=8.3, 6.8, 6.4, 3.4 Hz,1 H, 2-H), 7.01 (S_(br), 1 H, 6-OH), 7.14–7.39 (m, 9 H, 5-H, 8-H, 9-H,4×Ph-H_(m), 2×Ph-H_(p)), 7.46 (d, J=8.3 Hz, 1 H, 10-H), 7.62–7.67 (m, 4H, Ph-H_(o)), 7.97 (d, J=7.5 Hz, 1 H, 7-H).

¹³C-NMR (50 MHz, CDCl₃): δ=19.26 (SiC(CH₃)₃), 27.00 (SiC(CH₃)₃), 28.27(OC(CH₃)₃), 33.71 (C-1), 50.40 (C-3), 66.69 (C-2), 81.37 (OC(CH₃)₃),105.7 (C-5), 112.9 (C-10b), 122.2, 122.5, 123.7 (C-7, C-10, C-8), 122.7(C-6a), 126.5 (C-9), 127.7 (4×Ph-C_(m)), 129.8 (2×Ph-C_(p)), 132.7(C-10a), 133.8, 134.0 (2×Ph-C_(i)), 135.4 (C-4a), 135.7 (4×Ph-C_(o)),150.4 (C═O), 154.3 (C-6).

MS (DCI, NH₃): m/z (%)=571 (100) [M+NH₄]⁺.

C₃₄H₃₉NO₄Si (553.76). calc.: C: 73.74 H: 7.10 found: C: 73.53 H: 7.32

{4-[5′-((1H-indole-2″-carbonyl)-amino)-1H-indole-2′-carbonyl]-2-(tert-butyldiphenylsilanyloxy)-1,2,3,4-tetrahydrobenzo[f]quinolin-6-yl}-2*,3*,4*,6*-tetra-O-acetyl-β-D-galactopyranoside(4)

Phenol 3 (500 mg, 903 μmoles) andO-(2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl)-trichloroacetimidate(490 mg, 993 μmoles, 1.1 equivs.) were dissolved in absolute CH₂Cl₂ (50ml), stirred for ca. 30 minutes over a 4 Å molecular sieve and thencooled to −10° C. BF₃/OEt₂ (56.7 μl, 64.1 mg, 451 μmoles, 0.5 equiv.)was then added dropwise at this temperature, immediately producing ayellow colouration. After stirring for three hours at −10° C. furtherBF₃/OEt₂ were added (340 μl, 384 mg, 2.71 mmoles, 3.0 equivs.) and thewhole was heated to room temperature. Five hours later the reactionmixture was transferred via a transfer cannula to a second flask andthereby separated from the molecular sieve. The yellow solid remainingafter removal of the solvent by recondensation was dried for ca. 1 hourin vacuo and then taken up in absolute DMF (20 ml). After addition ofbisindole-carboxylic acid (288 mg, 903 μmoles, 1.0 equiv.) and EDC (519mg, 2.71 mmoles, 3.0 equivs.) the reaction mixture was stirred for 14hours at room temperature and the yellow precipitate thereby formed wasthen filtered off through a small amount of celite (post-rinsing withCH₂Cl₂). The filtrate was washed with water and saturated NaCl solution,dried over MgSO₄, and the solvent was removed in vacuo. After columnchromatography purification with PE/EE=3:2, 406 mg (41%) of the desiredproduct (4) were obtained as a yellow solid together with 120 mg (15%)of free amine.

R_(f)=0.14 (PE/EE=3:2), red (VSS);

UV (CH₃CN): λ_(max) (lg ε)=311 nm (3.588).

IR (KBr): ñ=3405 cm⁻¹ (NH), 3071 (Ar—H), 2932 (CH), 1753 (C═O), 1620(C═C), 1597, 1370, 1229, 1078, 745.

¹H-NMR (300 MHz, acetone-d₆): δ=1.00 (s, 9 H, C(CH₃)₃), 1.89, 1.95, 2.11(3×s, 12 H, 4×C(O)CH₃), 3.13–3.22 (m, 1 H, 1-H_(a)), 3.29 (dd, J=17.3,5.3 Hz, 1 H, 1-H_(b)), 3.58–3.69 (m, 1 H, 3-H_(a)), 3.82–4.07 (m, 3 H,6*-H₂, 5*-H), 4.09–4.30 (m, 1 H, 3-H_(b)), 4.51–4.58 (m, 1 H, 2-H), 4.70(d, J=8.0 Hz, 1 H, 1*-H), 4.87 (dd, J=10.5, 3.4 Hz, 1 H, 3*-H), 5.31(dd, J=7.5, 3.4 Hz, 1 H, 4*-H), 5.40 (dd, J=10.5, 8.0 Hz, 1 H, 2*-H),6.68 (s, 1 H, 3′-H), 7.01–7.04 (m, 1 H, 5″-H), 7.06 (s, 1 H, 5-H),7.18–7.69 (m, 18 H, Ph-H, 3″-H, 4″-H, 6″-H, 7″-H, 6′-H, 7′-H, 8-H, 9-H),7.80 (dd, J=8.9, 8.9 Hz, 1 H, 10-H), 7.99–8.04 (m, 1 H, 7-H), 8.24 (s, 1H, 4′-H), 9.46 (s, 1H, 5′-NH), 10.70 (s, 1 H, indole-NH), 10.91 (s, 1H,indole-NH).

¹³C-NMR (50 MHz, acetone-d₆): δ=15.56 (C(CH₃)₃), 20.44 (3×CHOC(O)CH₃),20.70 (CH₂OC(O)CH₃), 27.30 (C(CH₃)₃), 33.39 (C-1), 51.56 (C-3), 61.96(C-6*), 67.20 (C-2), 67.92 (C-4*), 69.01 (C-2*), 71.36 (C-3*), 71.63(C-5*), 101.3 (C-1*), 103.7 (C-3″), 108.0 (C-3′), 109.2 (C-5), 113.0,113.1 (C-6′, C-7′), 113.9 (C-4′), 116.9 (C-10b), 120.1 (C-5″), 120.9,125.9, 128.0, 130.6 (C-7, C-10, C-4″, C-7″), 122.5, 123.6 (C-8, C-9),124.6 (C-6a), 124.7 (C-6″), 128.2, 128.7 (C-3′a, C-3″a), 128.5(4×Ph-C_(m), 2×Ph-C_(p)), 132.5, 132.9, 133.0, 133.7, 134.1, 134.4(C-10a, 2×Ph-C_(i), C-5′, C-2′, C-2″, C-7′a), 136.5 (4×Ph-C_(o)), 136.8,137.9 (C-7″a, C-4a), 151.7 (C-6), 160.6 (2′-C═O), 164.1 (2″-C═O), 170.2,170.6, 170.7, 170.9 (4×C(O)—CH₃).

MS (DCI, NH₃): m/z (%)=1102 (100) [M+NH₄]⁺, 1085 (38) [M+H]⁺.

C₆₁H₆₀N₄O₁₃Si (1085.23). calc.: C: 67.51 H: 5.57 N: 5.16 found: C: 67.69H: 5.45 N: 5.05

4-[5′-((1H-indole-2″-carbonyl)-amino)-1H-indole-2′-carbonyl]-2-hydroxy-1,2,3,4-tetrahydro-benzo[f]quinolin-6-yl}-2*,3*,4*,6*-tetra-O-acetyl-β-D-galactopyranoside(5)

The silyl ether 4 (300 mg, 276 μmoles) was dissolved in absolute THF (10ml), was added together with TBAF to silica gel (754 mg, 829 μmoles, 3equivs.) and the whole was stirred for six hours at room temperature.The reaction mixture was worked up by adding three small spatula amountsof silica gel and the solvent was removed in vacuo. The residue waspurified by column chromatography with PE/EE=1:1→1:5 and yielded 111 mg(47%) of pure alcohol 5 as a yellowish solid.

R_(f)=0.33 (PE/EE=1:5)

UV (CH₃CN): λ_(max) (lg ε)=214 nm (3.772), 240 (3.638), 310 (3.630).

IR (KBr): ñ=3396 cm⁻¹ (NH), 3283 (OH), 3075 (Ar—H), 2932 (CH), 1752(C═O), 1619 (C═C), 1597, 1370, 1230, 1075, 750.

¹H-NMR (300 MHz, acetone-d₆): δ=1.88, 1.94, 1.95, 2.10 (4×s, 12 H,4×C(O)CH₃), 3.09 (dd, J=17.0, 6.8 Hz, 1 H, 1-H_(a)), 3.51 (dd, J=17.0,6.4 Hz, 1 H, 1-H_(b)), 3.62–3.72 (m, 2 H, 5*-H, 3-H_(a)), 3.92–4.03 (m,2 H, 6*-H₂), 4.40 (d, J=8.0 Hz, 1 H, 1*-H), 4.43–4.51 (m, 1 H, 2-H),4.54 (d, J=4.2 Hz, 1 H, OH), 4.56 (dd, J=14.3, 3.4 Hz, 1 H, 3-H_(b)),4.72 (dd, J=10.6, 3.4 Hz, 1 H, 3*-H), 5.29 (dd, J=6.8, 3.4 Hz, 1 H,4*-H), 5.33 (dd, J=10.6, 8.0 Hz, 1 H, 2*-H), 6.73 (d, J=1.1 Hz, 1 H,3′-H), 6.86 (s, 1 H, 5-H), 7.07 (ddd, J=7.9, 7.9, 1.1 Hz, 1 H, 5″-H),7.23 (ddd, J=7.9, 7.9, 1.1 Hz, 1 H, 6″-H), 7.30 (s, 1 H, 3″-H),7.45–7.66 (m, 6 H, 4″-H, 7″-H, 6′-H, 7′-H, 8-H, 9-H), 7.95–8.02 (m, 2 H,7-H, 10-H), 8.24 (d, J=1.1 Hz, 1 H, 4′-H), 9.38 (s_(br), 1H, 5′-NH),10.70 (s, 1 H, indole-NH), 10.83 (s, 1H, indole-NH).

¹³C-NMR (75 MHz, acetone-d₆): δ=20.53 (3×CHOC(O)CH₃), 20.71(CH₂OC(O)CH₃), 33.86 (C-1), 51.66 (C-3), 61.99 (C-6*), 65.72 (C-2),67.89 (C-4*), 69.01 (C-2*), 71.40 (C-3*), 71.59 (C-5*), 101.6 (C-1*),108.0 (C-3″), 109.1 (C-3′), 113.0 (C-5), 113.1, 113.2 (C-6′, C-7′),113.9 (C-4′), 118.1 (C-10b), 120.1, 120.9, 125.9, 128.1 (C-8, C-9, C-4″,C 7″), 120.2 (C-5″), 122.6, 123.9 (C-7, C-10), 124.5 (C-6a), 124.7(C-6″), 128.7, 128.8 (C-3′a, C-3″a), 132.9, 133.0, 133.1, 133.8, 134.5,136.8, 137.8 (C-10a, C-5′, C-2′, C-2″, C-7′a, C-7″a, C-4a), 151.9 (C-6),160.5 (2′-C═O), 163.8 (2″-C═O), 170.1, 170.3, 170.6, 170.7 (4×C(O)—CH₃).

MS (ESI): m/z (%)=869 (100) [M+Na]⁺, 1715 (33) [2M+Na]⁺.

C₄₅H₄₂N₄O₁₃ (846.84). calc.: C: 63.81 H: 5.00 N: 6.62 found: C: 63.53 H:5.27 N: 6.46

{2-chloro-4-[5′-((1H-indole-2″-carbonyl)-amino)-1H-indole-2′-carbonyl]-1,2,3,4-tetrahydro-benzo[f]quinolin-6-yl}-2*,3*,4*,6*-tetra-O-acetyl-β-D-galactopyranoside(6)

Solid triphenylphosphane (557 mg, 2.13 mmoles, 6 equivs.) was added to asolution of the alcohol 5 (300 mg, 354 μmoles) in a mixture of absoluteCCl₄ and CH₃CN (1:1, 12 ml) and the reaction mixture was stirred forfour hours at 40° C. After addition of about three spatula amounts ofsilica gel the solvent was removed in vacuo and the residue waschromatographed with toluene/acetone=2:1. A total of 226 mg (74%) of amixture of the desired chloride 6 and the corresponding eliminationproduct (ratio ca. 2:1 ) was thereby obtained, from which, after renewedchromatography (PE/EE=1:1→3:1), 116 mg (38%) of the diastereomer-purechloride 6a could be isolated as a pale yellow solid. The combined mixedfractions consisting of the second diastereomer and the correspondingelimination product were separated by semi-preparative HPLC (conditionssee below). The product fractions thereby obtained were saturated withwater, extracted three times with CH₂Cl₂ and the combined organic phaseswere finally concentrated by evaporation-in vacuo. Any traces of waterpresent were removed by azeotropic distillation with benzene.

Analytical Data for the First Diastereomer 6a:

R_(f)=0.13 (PE/EE =1:1).

UV (CH₃CN): λ_(max) (lg ε)=213 nm (3.804), 239 (3.695), 311 (3.673).

IR (KBr): ñ=3348 cm⁻¹ (NH), 3074 (Ar—H), 2934 (CH), 1752 (C═O), 1621(C═C), 1598, 1370, 1230, 747.

¹H-NMR (300 MHz, acetone-d₆): δ=1.94, 1.96, 2.00, 2.15 (4×s, 12H,4×C(O)CH₃), 3.47–3.56 (m, 2H, 1-H₂), 3.76–4.10 (m, 3H, 5*-H, 6*-H₂),4.14 (dd, J=12.8, 7.2 Hz, 1H, 3-H_(a)), 4.59 (d, J=8.3 Hz, 1H, 1*-H),4.67 (dd, J=12.8, 2.6 Hz, 1H, 3-H_(b)), 4.85 (dd, J=10.5, 3.4 Hz, 1H,3*-H), 4.49–5.02 (m, 1H, 2-H), 5.35 (d, J=3.0 Hz, 1H, 4*-H), 5.41 (dd,J=10.5, 8.3 Hz, 1H, 2*-H), 6.80 (s, 1H, 3′-H), 6.97 (s, 1H, 5-H), 7.11(ddd, J=7.9, 7.9, 1.1Hz, 1H, 5″-H), 7.26 (ddd, J=7.2, 7.2, 1.1 Hz, 1H,6″-H), 7.37 (s, 1H, 3″-H), 7.53–7.71 (m, 6 H, 4″-H, 7″-H, 6′-H, 7′-H,8-H, 9-H), 8.01–8.08 (m, 2H, 7-H, 10 H), 8.31 (d, J=1.9 Hz, 1H, 4′-H),9.52 (s, 1H, 5′-NH), 10.92 (s, 1H, indole-NH), 10.96 (s, 1H, indole-NH).

¹³C-NMR (75 MHz, acetone-d₆): δ=20.53 (3×CHOC(O)CH₃), 20.70(CH₂OC(O)CH₃), 35.02 (C-1), 51.37 (C-3), 54.85 (C-2), 61.84 (C-6*),67.83 (C-4*), 69.05 (C-2*), 71.36 (C-3*), 71.59 (C-5*), 101.5 (C-1*),103.7 (C-3″), 108.4 (C-3′), 109.1 (C-5), 113.1, 113.2 (C-6′, C-7′),113.9 (C-4′), 116.3 (C-10b), 120.4, 120.9, 122.6, 122.7, 123.7, 124.7,126.1, 128.4 (C-7, C-8, C-9, C-10, C-4″, C-5″, C-6″, C-7″), 128.1(C-6a), 128.7, 128.8 (C-3′a, C-3″a), 132.4, 132.9, 133.1, 133.4, 134.6,136.4, 137.8 (C-10a, C-5′, C-2′, C-2″, C-7′a, C-7″a, C-4a), 152.1 (C-6),160.6 (2′-C ═O), 164.0 (2″-C═O), 170.1, 170.3, 170.6, 170.7(4×C(O)—CH₃).

MS (DCI, NH₃): m/z (%)=882 (100) [M+NH₄]⁺, 865 (22) [M+H]⁺.

C₄₅H₄₁N₄O₁₂Cl (865.29). calc.: C: 62.46 H: 4.78 found: C: 62.14 H: 5.14

Analytical data for the second diastereomer 6b: HPLC (semi- column:Kromasil 100 C18, 5 μm, 250 × 8 mm preparative): eluent: 72% methanol inH₂O; 2.0 ml/min Rt: 29.74 min

¹H-NMR (300 MHz, acetone-d₆): δ=1.87, 1.94, 1.98, 2.10 (4×s, 12H,4×C(O)CH₃), 3.50–3.56 (m, 2H, 1-H_(a), 3-H_(a)), 3.87 (dd, J=18.1, 5.6Hz, 1H, 1-H_(b)), 3.97–4.03 (m, 3H, 5*-H, 6*-H₂), 4.32 (d, J=7.9 Hz, 1H,1*-H), 4.65 (dd, J=10.6, 3.4 Hz, 1H, 3*-H), 4.93 (dd, J=13.2, 3.8 Hz,1H, 3-H_(b)), 5.10 (m_(c), 1H, 2-H), 5.27 (dd, J=3.8, 1.2 Hz, 1H, 4*-H),5.32 (dd, J=10.6, 7.9 Hz, 1H, 2*-H), 6.73 (d, J=1.9 Hz, 1H, 3′-H), 6.83(s, 1H, 5-H), 7.05–7.10 (m, 1H, 5″-H), 7.19–7.25 (m, 1H, 6″-H), 7.30 (d,J=1.9 Hz, 1H, 3″-H), 7.50–7.67 (m, 6 H, 4″-H, 7″-H, 6′-H, 7′-H, 8-H,9-H), 7.95–8.00 (m, 2H, 7-H, 10-H), 8.28 (s,1H, 4′-H), 9.37 (s, 1H,5′-NH), 10.74 (s_(br), 1H, indole-NH), 10.84 (s_(br), 1H, indole-NH).

¹³C-NMR (125 MHz, acetone-d₆): δ=20.47, 20.48, 20.58, 20.71 (4×C(O)CH₃),34.66 (C-1), 50.81 (C-3), 55.94 (C-2), 62.10 (C-6*), 67.87 (C-4*), 68.86(C-2*), 71.38 (C-3*), 71.61 (C-5*), 101.6 (C-1*), 103.6 (C-3″), 108.5(C-3′), 108.9 (C-5), 113.1, 113.3 (C-6′, C-7′), 113.9 (C-4′), 114.9(C-10b), 120.4, 120.9, 122.5, 122.6, 123.7, 124.7, 126.1, 128.4 (C-7,C-8, C-9, C-10, C-4″, C-5″, C-6″, C-7″), 124.5 (C-6a), 128.1, 128.8(C-3′a, C-3″a), 132.5, 133.0, 133.2, 133.6, 134.6, 136.4, 137.9 (C-10a,C-5′, C-2′, C-2″, C-7′a, C-7″a, C-4a), 152.2 (C-6), 160.5 (2′-C═O),164.4 (2″-C═O), 170.2, 170.3, 170.6 170.7 (4×C(O)—CH₃).

rac-{2-chloro-4-[5′-((1H-indole-2″-carbonyl)-amino)-1H-indole-2′-carbonyl]-1,2,3,4-tetrahydrobenzo[f]quinolin-6-yl}-β-D-galactopyranoside(7):

The acetyl-protected galactoside 6 (40.0 mg, 46.2 μmoles) was dissolvedin absolute methanol (1.5 ml) and NaOMe (3.77 μl of a 5.4 M solution inMeOH, 20.3 μmoles, 0.44 equiv.) was added at 0° C. After discontinuingthe cooling the reaction mixture was stirred for 30 minutes at roomtemperature and the product was then precipitated by adding water. Theprecipitate was filtered off with a P2 frit and washed with water. Inorder to remove traces of water the solid was suspended three times intoluene and the solvent was removed in vacuo. 30.5 mg (95%) ofdeprotected galactoside 7 were obtained in the form of a pale yellowishsolid.

R_(f)=0.28 (EE/MeOH=10:1)

UV (CH₃CN) : λ_(max) (lg ε)=215 nm (3.575), 310 (3.431).

IR (KBr): ñ=3406 cm⁻¹ (very broad, NH/OH), 3077 (Ar—H), 2924 (CH), 1622(C═C), 1530, 14.04, 1233, 1074 748.

¹H-NMR (500 MHz, DMF-d₇): δ=3.28–3.31 (m, 2H, 3*-H, 5*-H), 3.47 (dd,J=17.6, 4.8 Hz, 1H, 1-H_(a)), 3.58 (dd, J=11.0, 6.0 Hz, 1H, 6*-H_(a)),3.65 (dd, J=11.0, 6.4 Hz, 1H, 6*-H_(b)), 3.82–3.88 (m, 2H, 2*-H, 4*-H,1-H_(b)), 4.43 (dd, J=12.8, 6.4 Hz, 1H, 3-H_(a)), 4.45–4.49 (m, 2H,1*-H, 3-H_(b)), 5.01–5.05 (m, 1H, 2-H), 6.82 (d, J=1.4 Hz, 1H, 3′-H),7.09 (ddd, J=6.9, 6.9, 0.9 Hz, 1H, 5″-H), 7.17 (s, 1H, 5-H), 7.25 (ddd,J=7.1, 6.9, 1.0 Hz, 1H, 6″-H), 7.48 (m, 3H, 3″-H, 7′-H, 8-H), 7.58–7.64(m, 2H, 7″-H, 9-H), 7.68 (d, J=6.9 Hz, 1H, 4″-H), 7.69 (d, J=6.9, 1.9Hz, 1H, 6′-H), 7.97 (d, J=8.5 Hz, 1H, 10-H), 8.19 (d, J=1.9 Hz, 1H,4′-H), 8.37 (d, J=8.5 Hz, 1H, 7-H), 10.20 (s, 1H, 5′-NH), 11.67 ( s, 2H,2×indole-NH).

¹³C-NMR (125 MHz, DMF-d₇): δ=39.33 (C-1), 51.87 (C-3), 55.54 (C-2),61.53 (C-6*), 69.30, 71.69 (C-4*, C-2*), 74.54 (C-3*), 76.22 (C-5*),103.9 (C-1*, C-3″), 107.4 (C-3′), 108.9 (C-5), 112.9, 113.0 (C-7′,C-7″), 113.4 (C-4′), 114.4 (C-10b), 119.6 (C-6′), 120.5 (C-5″), 122.3(C-4″), 123.2 (C-7), 123.5 (C-10), 124.2 (C-6″), 124.8 (C-6a), 125.2(C-8), 127.8 (C-9), 128.5, 128.8 (C-3′a, C-3″a), 129.6 (C-7′a), 132.6,133.0, 133.1, 134.7, (C-10a, C-5′, C-2′, C-2″), 136.5, 137.8 (C-7″a,C-4a), 152.4 (C-6), 160.5 (2′-C═O), 164.5 (2″-C═O).

MS (FAB): m/z (%)=695 (100) [M−H]⁻.

C₃₇H₃₃N₄O₈Cl (697.14). calc.: C: 63.75 H: 4.77 found: C: 63.71 H: 4.85Analytical HPLC for determination column: Kromasil 100 C18 of thepurity: eluent: 62% MeOH in H₂O; 0.7 ml/min RT: 41.65 min

The invention claimed is: 1.5-hydroxy-1,2-dihydro-3H-pyrrolo[3,2-e]indoles of the general formula(II) or 5-hydroxy-1,2-dihydro-3H-benzo[e]indoles of the general formula(III), or their O-glycosides with monosaccharides, disaccharides oroligosaccharides of the general formulae (V) and (VI):

wherein in the general formulae (II), (III), (V) and (VI) R¹ denoteshalogen R² denotes straight-chain or branched alkyl with up to 8 carbonatoms, which is optionally substituted by phenyl, hydroxy,straight-chain or branched alkoxy with up to 6 carbon atoms, R³ denotesstraight-chain or branched alkyl with up to 8 carbon atoms, which isoptionally substituted by phenyl, hydroxy, straight-chain or branchedalkoxy with up to 6 carbon atoms, or denotes a group of the formula—SO₂R⁸, —CO—R⁹ or —CO₂R¹⁰, wherein R⁸ denotes straight-chain or branchedalkyl with up to 6 carbon atoms, benzyl or phenyl, the latter optionallybeing substituted by straight-chain or branched alkyl with up to 6carbon atoms, and R⁹ denotes straight-chain or branched alkyl with up to8 carbon atoms, which is optionally substituted by carboxy,straight-chain or branched alkoxycarbonyl with up to 6 carbon atoms, orby a group of the formula —CO—NR¹¹R¹², wherein the radicals R¹¹ and R¹²together form a biradical of one of the following formulae

wherein R^(1′), R^(2′), R^(4′), R^(5′), R^(6′) and R^(7′) have themeanings of R¹, R², R⁴, R⁵, R⁶ and R⁷ given above and hereinafter,wherein R^(2′) also denotes hydrogen, R¹⁰ denotes hydrogen orstraight-chain or branched alkyl with up to 6 carbon atoms, or R³denotes a radical of one of the formulae

wherein R^(1″), R^(2″) have the meanings of R¹, R² given above, R^(4″)denotes hydrogen or straight-chain or branched alkyl with up to 8 carbonatoms, which is also optionally substituted by hydroxy, carboxy, phenylor by straight-chain or branched alkoxy, acyl or alkoxycarbonyl with ineach case up to 6 carbon atoms, or denotes a hydroxy or amino group thatis optionally substituted by straight-chain or branched alkyl, acyl oralkoxycarbonyl with in each case up to 6 carbon atoms, R^(5″) denotes amonosaccharide, disaccharide or oligosaccharide of hexoses or pentosesor heptoses, that may also be included among the group of desoxy sugarsor amino sugars and belong to the D-series or L-series and in thedisaccharides or oligosaccharides are either identical or different,R^(6″) and R^(7″) are identical or different and denote hydrogen orstraight-chain alkyl with up to 8 carbon atoms, R⁴, R⁵, R⁶and R⁷ havethe meanings of R^(4″), R^(5″), R^(6″) and R^(7″) given above, R¹³, R¹⁴and R¹⁵ are identical or different and denote hydrogen or straight-chainor branched alkyl or acyl with in each case up to 6 carbon atoms, R¹⁶denotes unsubstituted nitrogen, oxygen or sulfur, R¹⁷ denotes ahydroxy-protective group, or straight-chain or branched alkyl with up to8 carbon atoms that is optionally substituted by hydroxy, carboxyl,phenyl or by straight-chain or branched alkoxyl, acyl or alkoxycarbonylwith in each case up to 6 carbon atoms, and optionally together with R⁴,R⁵ or R⁶ forms a ring, or denotes a sugar residue of the formula

in the D or L form, wherein R²¹ denotes methyl or the —CH₂OH group andR²² denotes hydroxyl or a radical of the formula —NR²³R²⁴, wherein R²³and R²⁴ are identical or different and denote hydrogen, straight-chainor branched alkyl with up to 6 carbon atoms or an amino-protectivegroup, and wherein the hydroxyl groups of the sugar residues areoptionally protected, R¹⁸, R¹⁹ and R²⁰ are identical or different anddenote hydrogen or straight-chain or branched or cyclic alkyl with up to8 carbon atoms that is optionally substituted by phenyl, halogen, azido,straight-chain or branched alkoxyl, alkoxycarbonyl or oxyacyl with ineach case up to 6 carbon atoms, hydroxyl, carbonyl or by a group of theformula —NR²³R²⁴, wherein R²³ and R²⁴ have the meaning given above.
 2. Acompound of the general formula (II), (III), (V) or (VI) according toclaim 1, wherein R¹ denotes chlorine, bromine or iodine, R² denotesstraight-chain or branched alkyl with up to 8 carbon atoms that isoptionally substituted by phenyl, hydroxy, straight-chain or branchedalkoxy with up to 4 carbon atoms, R³ denotes straight-chain or branchedalkyl with up to 6 carbon atoms, which is optionaliy substituted byphenyl, hydroxy, straight-chain or branched alkoxy with up to 4 carbonatoms, or denotes a group of the formula —SO₂R⁸, —COR⁹ or —CO₂R¹⁰,wherein R⁸ denotes straight-chain or branched alkyl with up to 4 carbonatoms, benzyl or phenyl, wherein the latter are optionally substitutedby straight-chain or branched alkyl with up to 4 carbon atoms, and R⁹denotes straight-chain or branched alkyl with up to 6 carbon atoms whichis optionally substituted by carboxy, straight-chain or branchedalkoxycarbonyl with up to 4 carbon atoms, or by a group of the formula—CO—NR¹¹R¹², wherein R¹¹ and R¹² together form a biradical of one of thefollowing formulae

wherein R^(1′), R^(2′) have the meanings of R¹, R² given above, whereinR^(2′) also denotes a hydrogen atom, R^(4′) denotes hydrogen orstraight-chain or branched alkyl with up to 6 carbon atoms or denotes ahydroxy or amino group that is optionally substituted by astraight-chain or branched alkyl, acyl or alkoxycarbonyl with in eachcase up to 6 carbon atoms, R^(5′) denotes a monosaccharide or adisaccharide of hexoses or pentoses that may also be included among thegroup of desoxy sugars or amino sugars and belong to the D-series orL-series and may be either identical or different in the disaccharide,R^(6′) and R^(7′) are identical or different and denote hydrogen orstraight-chain alkyl with up to 8 carbon atoms, R¹⁰ denotes hydrogen orstraight-chain or branched alkyl with up to 6 carbon atoms, or R³denotes a radical of one of the formulae

wherein R^(1″), R^(2″) have the meanings of R¹, R² given above, R^(4″),R^(5″), R^(6″) and R^(7″) have the meanings of R^(4′), R^(5′), R^(6′)and R^(7′) given above, R¹³, R¹⁴ and R¹⁵ are identical or different anddenote hydrogen or straight-chain or branched alkyl or acyl with in eachcase up to 6 carbon atoms, R¹⁶ denotes unsubstituted nitrogen, oxygen orsulfur, R⁴ denotes hydrogen or straight-chain or branched alkyl with upto 6 carbon atoms or denotes a hydroxy or amino group that is optionallysubstituted by a straight-chain or branched alkyl, acyl oralkoxycarbonyl with in each case up to 6 carbon atoms, R⁵ denotes amonosaccharide or a disaccharide of hexoses or pentoses that may also beincluded among the group of desoxy sugars or amino sugars and belong tothe D-series or L-series and may be either identical or different in thedisaccharide, R⁶ and R⁷ are identical or different and denote hydrogenor straight-chain alkyl with up to 8 carbon atoms, R¹⁷ denotes ahydroxy-protective group, or straight-chain or branched alkyl with up to8 carbon atoms that is optionally substituted by hydroxy, carboxyl,phenyl or by straight-chain or branched alkoxyl, acyl or alkoxycarbonylwith in each case up to 6 carbon atoms, and optionally together with R⁴,R⁵ or R⁶ forms a ring, or denotes a sugar residue of the formula

in the D or L form, wherein R²¹ denotes methyl or the —CH₂OH group andR²² denotes hydroxyl or a radical of the formula —NR²³R²⁴, wherein R²³and R²⁴ are identical or different and denote hydrogen, straight-chainor branched alkyl with up to 6 carbon atoms or an amino-protectivegroup, and wherein the hydroxy groups of the sugar residues areoptionally protected, R¹⁸, R¹⁹ and R²⁰ are identical or different anddenote hydrogen or straight-chain or branched or cyclic alkyl with up to8 carbon atoms, which is optionally substituted by phenyl, halogen,azido, straight-chain or branched alkoxyl, alkoxycarbonyl or oxyacylwith in each case up to 6 carbon atoms, hydroxyl, carboxyl or by a groupof the formula —NR²³R²⁴, wherein R²³ and R²⁴ have the meaning givenabove.
 3. A compound of the general formula (II), (III), (V) or (VI)according to claim 1, wherein R¹ denotes chlorine, R² denotesstraight-chain or branched alkyl with up to 4 carbon atoms that isoptionally substituted by phenyl, hydroxy, straight-chain or branchedalkoxy with up to 3 carbon atoms, R³ denotes straight-chain or branchedalkyl with up to 4 carbon atoms that is optionally substituted byphenyl, hydroxy, straight-chain or branched alkoxy with up to 3 carbonatoms, or denotes a group of the formula —SO₂R⁸, wherein R⁸ denotesmethyl, benzyl or phenyl, the latter optionally being substituted bymethyl or ethyl or R³ denotes a radical or one of the formulae

wherein R^(1″), R^(2″), R^(4″), R^(5″), R^(6″) and R^(7″) have themeanings of R¹, R², R⁴, R⁵, R⁶ and R⁷ given above and hereinafter, R¹³,R¹⁴ and R¹⁵ are identical or different and denote hydrogen, methyl,ethyl or acetyl, R¹⁶ denotes unsubstituted nitrogen, oxygen or sulfur,R⁴ denotes hydrogen, R⁵ denotes α-D-mannose, β-D-galactose,β-D-glucuronic acid and β-D-glucose, R⁶ and R⁷ are identical ordifferent and denote hydrogen or a straight-chain or branched alkyl withup to 4 carbon atoms.
 4. A treatment agent containing a pharmaceuticallyacceptable carrier and one or more compounds selected from5-hydroxy-1,2-dihydro-3H-pyrrolo[3,2-e]indoles of the general formula(II) or 5hydroxy-1,2dihydro-3H-benzo[e]indoles of the general formula(III), or their O-glycosides with monosaccharides, disaccharides oroligosaccharides of the general formulae (V) and (VI):

wherein in the general formulae (II), (III), (V) and (VI) R¹ denoteshalogen, R² denotes straight-chain or branched alkyl with up to 8 carbonatoms, which is optionally substituted by phenyl, hydroxy,straight-chain or branched alkoxy with up to 6 carbon atoms, R³ denotesstraight-chain or branched alkyl with up to 8 carbon atoms, which isoptionally substituted by phenyl, hydroxy, straight-chain or branchedalkoxy with up to 6 carbon atoms, or denotes a group of the formula—SO₂R⁸, —CO—R⁹or —CO₂R¹⁰, wherein R⁸ denotes straight-chain or branchedalkyl with up to 6 carbon atoms, benzyl or phenyl, the latter optionallybeing substituted by straight-chain or branched alkyl with up to 6carbon atoms, and R⁹ denotes straight-chain or branched alkyl with up to8 carbon atoms, which is optionally substituted by carboxy,straight-chain or branched alkoxycarbonyl with up to 6 carbon atoms, orby a group of the formula —CO—NR¹¹R¹², wherein the radicals R¹¹ and R¹²together form a biradical of one of the following formulae

wherein R^(1′), R^(2′), R^(4′), R^(5′), R^(6′) and R^(7′) have themeanings of R¹, R², R⁴, R⁵, R⁶ and R⁷ given above and hereinafter,wherein R² also denotes hydrogen, R¹⁰ denotes hydrogen or straight-chainor branched alkyl with up to 6 carbon atoms, or R³ denotes a radical orone of the formulae

wherein R^(1″), R^(2″) have the meanings of R¹, R² given above, R^(4″)denotes hydrogen or straight-chain or branched alkyl with up to 8 carbonatoms, which is also optionally substituted by hydroxy, carboxy, phenylor by straight-chain or branched alkoxy, acyl or alkoxycarbonyl with ineach case up to 6 carbon atoms, or denotes a hydroxy or amino group thatis optionally substituted by straight-chain or branched alkyl, acyl oralkoxycarbonyl with in each case up to 6 carbon atoms, R^(5″) denotes amonosaccharide, disaccharide or oligosaccharide of hexoses or pentosesor heptoses, that may also be included among the group of desoxy sugarsor amino sugars and belong to the D-series or L-series and in thedisaccharides or oligosaccharides are either identical or different,R^(6″) and R^(7″) are identical or different and denote hydrogen orstraight-chain alkyl with up to 8 carbon atoms, R⁴, R⁵, R⁶ and R⁷ havethe meanings of R^(4″), R^(5″), R^(6″) and R^(7″) given above, R¹³, R¹⁴and R¹⁵ are identical or different and denote hydrogen or straight-chainor branched alkyl or acyl with in each case up to 6 carbon atoms, R¹⁶denotes unsubstituted nitrogen, oxygen or sulfur, R¹⁷ denotes ahydroxy-protective group, or straight-chain or branched alkyl with up to8 carbon atoms that is optionally substituted by hydroxy, carboxyl,phenyl or by straight-chain or branched alkoxyl, acyl or alkoxycarbonylwith in each case up to 6 carbon atoms, and optionally together with R⁴,R⁵ or R⁶ forms a ring, or denotes a sugar residue of the formula

in the D or L form, wherein R²¹ denotes methyl or the —CH₂OH group andR²² denotes hydroxyl or a radical of the formula —NR²³R²⁴, wherein R²³and R²⁴ are identical or different and denote hydrogen, straight-chainor branched alkyl with up to 6 carbon atoms or an amino-protectivegroup, and wherein the hydroxyl groups of the sugar residues areoptionally protected, R¹⁸, R¹⁹ and R²⁰ are identical or different anddenote hydrogen or straight-chain or branched or cyclic alkyl with up to8 carbon atoms that is optionally substituted by phenyl, halogen, azido,straight-chain or branched alkoxyl, alkoxycarbonyl or oxyacyl with ineach case up to 6 carbon atoms, hydroxyl, carbonyl or by a group of theformula —NR²³R²⁴, wherein R²³ and R²⁴ have the meaning given above.
 5. Aprocess for the production of a treatment agent, comprising:deprotonating an organic compound of the general formula (X) or (XI) atthe nitrogen atom of the —NHR³ group with a suitable base;

wherein R²⁵ denotes bromine or iodine, R²⁶ denotes one of thehydroxy-protective groups specified above, R³ denotes straight-chain orbranched alkyl with up to 8 carbon atoms, which is optionallysubstituted by phenyl, hydroxy, straight-chain or branched alkoxy withup to 6 carbon atoms, or denotes a group of the formula —SO₂R⁸, —CO—R⁹or —CO₂R¹⁰, wherein R⁸ denotes straight-chain or branched alkyl with upto 6 carbon atoms, benzyl or phenyl, the latter optionally beingsubstituted by straight-chain or branched alkyl with up to 6 carbonatoms, and R⁹ denotes straight-chain or branched alkyl with up to 8carbon atoms, which is optionally substituted by carboxy, straight-chainor branched alkoxycarbonyl with up to 6 carbon atoms, or by a group ofthe formula —CO—NR¹¹R¹², wherein the radicals R¹¹ and R¹² together forma biradical of one of the following formulae

wherein R^(1′), R^(2′), R^(4′), R^(5′), R^(6′) and R^(7′) have themeanings of R¹, R², R⁴, R⁵, R⁶ and R⁷ given above and hereinafter,wherein R^(2′) also denotes hydrogen, R¹⁰ denotes hydrogen orstraight-chain or branched alkyl with up to 6 carbon atoms, or R³denotes a radical of one of the formulae

wherein R¹ denotes halogen, R² denotes straight-chain or branched alkylwith up to 8 carbon atoms, which is optionally substituted by phenyl,hydroxy, straight-chain or branched alkoxy with up to 6 carbon atoms,R^(1″), R^(2″) have the meanings of R¹, R² given above, R^(4″) denoteshydrogen or straight-chain or branched alkyl with up to 8 carbon atoms,which is also optionally substituted by hydroxy, carboxy, phenyl or bystraight-chain or branched alkoxy, acyl or alkoxycarbonyl with in eachcase up to 6 carbon atoms, or denotes a hydroxy or amino group that isoptionally substituted by straight-chain or branched alkyl, acyl oralkoxycarbonyl with in each case up to 6 carbon atoms, R^(5″) denotes amonosaccharide, disaccharide or oligosaccharide of hexoses or pentosesor heptoses, that may also be included among the group of desoxy sugarsor amino sugars and belong to the D-series or L-series and in thedisaccharides or oligosaccharides arc either identical or different,R^(6″) and R^(7″) are identical or different and denote hydrogen orstraight-chain alkyl with up to 8 carbon atoms, R⁴, R⁵, R⁶ and R⁷ havethe meanings of R^(4″), R^(5″), R^(6″) and R^(7″) given above, R¹³, R¹⁴and R¹⁵ are identical or different and denote hydrogen or straight-chainor branched alkyl or acyl with in each case up to 6 carbon atoms, R¹⁶denotes unsubstituted nitrogen, oxygen or sulfur, R¹⁷ denotes ahydroxy-protective group, or straight-chain or branched alkyl with up to8 carbon atoms that is optionally substituted by hydroxy, carboxyl,phenyl or by straight-chain or branched alkoxyl, acyl or alkoxycarbonylwith in each case up to 6 carbon atoms, and optionally together with R⁴,R⁵ or R⁶ forms a ring, or denotes a sugar residue of the formula

in the D or L form, wherein R²¹ denotes methyl or the —CH₂OH group andR²² denotes hydroxyl or a radical of the formula —NR²³R²⁴, wherein R²³and R²⁴ are identical or different and denote hydrogen, straight-chainor branched alkyl with up to 6 carbon atoms or an amino-protectivegroup, and wherein the hydroxyl groups of the sugar residues areoptionally protected, R¹⁸, R¹⁹ and R²⁰ are identical or different anddenote hydrogen or straight-chain or branched or cyclic alkyl with up to8 carbon atoms that is optionally substituted by phenyl, halogen, azido,straight-chain or branched alkoxyl, alkoxycarbonyl or oxyacyl with ineach case up to 6 carbon atoms, hydroxyl, carbonyl or by a group of theformula —NR²³R²⁴, wherein R²³ and R²⁴ have the meaning given above,reacting the deprotonated organic compound of the general formula (X) or(XI) with a compound of the general formula (XII) or (XIII), in thepresence of an organic solvent to form a compound of the general formula(XV), (XVI), (XVIII) or (XIX),

wherein R¹ has the meaning given above, R² has the meaning given above,

wherein R¹ has the meaning given above, R² has the meaning given above,R³ has the meaning given above, R⁴, R⁶, R7, R²⁵ and R²⁶ have the meaninggiven above; closing the compound of the general formula (XV), (XVI),(XVIII) or (XIX) to form a dihydropyrrole ring by a radical cyclisationusing tributyltin hydride and a radical initiator; and removing theprotective group on the phenolic oxygen by hydrogenolysis in thepresence of Pd/C and ammonium formate, whereby a5-hydroxy-1,2dihydro-3H-pyrrolo[3,2-e]indole of the general formula (II)or 5-hydroxy-1,2-dihydro-3H-benzo[e]indole of the general formula (III)is formed,


6. A process according to claim 5, wherein R¹ in the general formula(II) or (III) denotes chlorine.
 7. A process according to claim 5,wherein R³ in the general formula (II) or (III) denotestert-butoxycarbonyl.
 8. A process according to claim 5, furthercomprising: reacting the compound of the general formula (II) or (III)with a protected monosaccharide, disaccharide or oligosaccharide thatcarries a trichloroacetimidate group, a halogen atom or anotherdeparting group on the C₁ atom, whereby a compound of the generalformula (V′) or (VI′), an O-glycoside of a compound of general formula(II) or (III), is formed,

wherein R¹, R², R⁴, R⁵, R⁶, and R⁷ are as defined in claim 5 and R^(3*)has the meaning of R³ and also denotes hydrogen.
 9. The method of claim8, further comprising: reacting the compound of general formula (V′) or(VI′) with a heteroaromatic carboxylic acid in an organic solvent in thepresence of a promoter, and for individual derivatisation steps also inthe presence of a base, whereby a compound of general formula (V) or(VI) is formed,

wherein R¹, R², R⁴, R⁵, R⁶ and R⁷ are as defined in claim 1 and R³ is aheteroaromatic carbonyl group.